2. INCRETIN SYSTEM IN TREATMENT OF TYPE 2 DM
regulating gastric emptying,11,12 and reducing food intake
by postulated centrally mediated mechanisms.10,13
Enzymatic inactivation by dipeptidyl peptidase 4
(DPP-4) shortens the biologic activity of GLP-1 to less
than 2 minutes.14 Glucagon-like peptide 1 controls fasting
and PPG concentrations by multiple actions, primarily by
stimulating glucose-dependent insulin secretion from pancreatic β cells while inhibiting glucagon secretion. In addition, GLP-1 enhances satiety and reduces food intake.
Among the newest approved classes of antidiabetes
medications are incretin-based therapies known as GLP-1
receptor agonists and DPP-4 inhibitors. Several medications in this category that recently have been approved by
the US Food and Drug Administration (FDA) have been
rapidly adopted into clinical practice.4
Exenatide is a GLP-1 receptor agonist that received
FDA approval in 2005 as an adjunct to diet and exercise
to improve glycemic control in adults with type 2 DM. Exenatide is indicated for use as monotherapy, but it may also
be used in combination with metformin plus a sulfonylurea
or metformin plus a thiazolidinedione.15 In January 2010,
liraglutide, another GLP-1 receptor agonist, received regulatory approval in the United States as an adjunct to diet and
exercise to improve glycemic control in adults with type 2
DM. Although not recommended for use as monotherapy,
liraglutide can be prescribed to patients who are metformin
intolerant or in whom metformin may be contraindicated.
Both exenatide and liraglutide are available for use as subcutaneous injections. Two DPP-4 inhibitors, sitagliptin and
saxagliptin, approved in 2006 and 2009, respectively, are
available orally for improving glycemic control in patients
with type 2 DM.
RELATIONSHIP OF GLP-1 DEFICIENCY AND
RESISTANCE TO THE PATHOGENESIS OF TYPE 2 DM
The fundamental pathophysiologic defects in type 2 DM
are β-cell failure and insulin resistance in muscle, the liver,
and adipose tissue.16 The metabolic consequences of these
deficits include impaired insulin secretion, decreased muscle glucose uptake, unrestrained hepatic glucose production, decreased hepatic glucose uptake, and inappropriate
secretion of glucagon. Diminished gastrointestinal production of incretins also plays a key role in the development
of hyperglycemia.16 Chronic hyperglycemia is the physiologic hallmark of type 2 DM and may be present before
the onset of clinical symptoms, causing pathologic and
functional changes in target organs and tissues.17
The 2 most important incretins are GLP-1 and glucosedependent insulinotropic polypeptide (GIP). Together
these hormones account for up to 70% of postprandial insulin secretion.18,19 The incretin effect is severely impaired
or absent in patients with type 2 DM, and recognition of the
important role of this effect in maintaining glucose homeostasis has fueled the current interest in the development of
therapies that target the incretin system.18
The impaired incretin effect in patients with type 2 DM
occurs in the presence of normal GIP secretion, suggesting a possible loss of β-cell sensitivity to the insulinotropic
effects of GIP in type 2 DM in addition to hyposecretion
or decreased sensitivity to incretin factors.20 The incretin
defect in patients with type 2 DM includes a lack of GIP
amplification of the late-phase (ie, 20- to 120-minute postprandial) insulin response to glucose.21 In contrast, there
is a moderate degree of GLP-1 hyposecretion in patients
with type 2 DM, although the insulinotropic response to
GLP-1 is well preserved.22 These observations provide a
rationale for the development of therapeutic options for the
modulation of the incretin effect via the GLP-1 pathway,
including degradation-resistant GLP-1 receptor agonists
(incretin mimetics) and inhibitors of DPP-4 activity (incretin enhancers).23
GLP-1 RECEPTOR AGONISTS AND
DPP-4 INHIBITORS
Exenatide is a GLP-1 receptor agonist that enhances glucose-dependent insulin secretion by the pancreatic β cells,
suppresses inappropriately elevated glucagon secretion,
and slows gastric emptying. Exenatide is a synthetic form
of exendin 4, a naturally occurring GLP-1 receptor agonist
found in the salivary secretions of the Gila monster.2 Exendin 4 is 53% homologous with human GLP-1 and binds to
the mammalian GLP-1 receptor with affinity equal to that
of native GLP-1, producing many of the same glucoregulatory effects.2,24 The amino acid sequence of exenatide partially overlaps that of human GLP-1, allowing the drug to
bind and activate human GLP-1 receptors, while delaying
DPP-4 degradation. Exenatide is resistant to degradation by
DPP-4 and detectable in the circulation for up to 10 hours
after administration, allowing for twice-daily administration in the treatment of patients with type 2 DM.2,24
Liraglutide’s structural modifications delay DPP-4 degradation, resulting in a half-life of 13 hours.25 Once bound
to the receptor, the GLP-1 receptor agonist increases insulin synthesis and release by mechanisms involving cyclic
adenosine monophosphate and other intracellular signaling
pathways.
Additional GLP-1 analogues are currently undergoing
clinical trials in the United States. Pharmaceutical companies are also looking into novel delivery mechanisms by
which these drugs might be shown to have better efficacy
and tolerability, such as continuous subcutaneous infusion
and implantable delivery systems.
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3. INCRETIN SYSTEM IN TREATMENT OF TYPE 2 DM
The DPP-4 inhibitors inhibit the proteolytic inactivation of GLP-1 by DPP-4. Unlike GLP-1 receptor agonists,
which result in pharmacological levels of GLP-1 (6- to
10-fold increase), DPP-4 inhibitors result in physiologic
levels of GLP-1 (2- to 3-fold increase).26 Physiologic increases in GLP-1 refer to the increase in hormone release
from the intestinal L cells, which would be expected to
occur in response to the ingestion of a carbohydrate-rich
meal in a euglycemic individual. Pharmacological activation of GLP-1 receptors occurs once agonists bind to them
and their actions are expressed by the receptor. The DPP-4
inhibitors prevent the degradation of GIP and a wide range
of other peptides, including chemokines, glucagon-secretin
family hormones, pancreatic polypeptide proteins, and neuropeptides.24 In contrast to GLP-1 receptor agonists, DPP-4
inhibitors do not affect gastric emptying, as reflected by the
lack of effect of DPP-4 inhibition on the rate of increase in
circulating glucose after ingestion of a meal.27
After initial animal studies and successful proof-ofconcept and clinical studies in humans, 2 DPP-4 inhibitors have been approved for marketing in the United States.
Both sitagliptin and saxagliptin are oral tablet formulations
taken once daily. A single-tablet formulation of sitagliptin
and metformin was approved in March 2007. In addition,
a new drug application has been filed in the United States
for a combination of saxagliptin and metformin. Finally, a
new drug application has been filed for vildagliptin, which
is approved in the European Union and Latin America for
the treatment of patients with type 2 DM. Alogliptin is also
being developed for use in patients with type 2 DM.
The DPP-4 inhibitors do not bind directly to GLP-1 receptors and have less potent pharmacological activity than
GLP-1 receptor agonists.2 They also impede the proteolytic
degradation of GLP-1 by binding directly to the DPP-4 enzyme, thereby increasing the concentration of endogenous
GLP-1 approximately 2-fold.2
In Table 2 of his article (also published in this supplement), Davidson28 reviews the comparative physiologic
and clinical effects of GLP-1 receptor agonists and DPP-4
inhibitors. The differences between these 2 groups of
compounds have been reflected in their distinct effects on
metabolic parameters and clinical end points observed in
comparative randomized trials. In a double-blind study,
95 patients with type 2 DM receiving metformin were
randomized to receive exenatide or sitagliptin for 2 weeks
and were then crossed over to the alternate therapy. After
2 weeks of exenatide, 2-hour PPG levels were lower with exenatide than with sitagliptin (133 vs 208 mg/dL; P<.0001).
Switching from exenatide to sitagliptin increased 2-hour
PPG by +73 mg/dL, whereas switching from sitagliptin
to exenatide further reduced 2-hour PPG by –76 mg/dL.
Postprandial insulin secretion was significantly greater with
exenatide than sitagliptin (P=.0017), and exenatide suppression of postprandial glucagon secretion was significantly
greater with exenatide than with sitagliptin (P=.0011).29
Exenatide demonstrated a significant slowing of gastric
emptying compared with baseline and sitagliptin (P<.0001)
and significantly reduced caloric intake compared with
sitagliptin (–134 vs +130 kcal per meal; P=.02).
In the Diabetes Therapy Utilization: Researching
Changes in A1c, Weight and Other Factors Through Intervention With Exenatide Once Weekly (DURATION-2),30
491 patients with type 2 DM following a stable regimen
of metformin were randomized to once-weekly treatment
with exenatide (n=160), sitagliptin (n=166), or pioglitazone
(n=165) for 26 weeks. Exenatide produced significantly
greater improvements in glucose control with mean reductions in hemoglobin A1c (HbA1c) levels of –1.55%, –0.92%,
and –1.23% with exenatide, sitagliptin, and pioglitazone,
respectively (P<.05 for both vs exenatide). Also, 66% of
patients receiving exenatide achieved an HbA1c level less
than 7% compared with 42% who received sitagliptin and
56% who received pioglitazone (P<.05 for both vs exenatide). Exenatide-associated reduction of body weight (–2.7
kg) was significantly greater that that seen with sitagliptin
or pioglitazone (–0.9 and +3.2 kg, respectively; P<.05 for
both vs exenatide).30
A recent clinical trial compared 2 daily doses of liraglutide, 1.2 mg (n=225) and 1.8 mg (n=221), with 100 mg
of sitagliptin (n=219) daily for 26 weeks in a randomized,
parallel-group, open-label fashion.31 Patients with type 2
DM inadequately controlled with metformin with a mean
baseline HbA1c level of 8.5% were studied. Greater lowering of HbA1c from baseline was seen with liraglutide,
1.2 mg (–1.24%; 95% confidence interval [CI], –1.37%
to –1.11%) and 1.8 mg (–1.50%; 95% CI, –1.63% to
–1.37%), than with sitagliptin (–0.90%; 95% CI, –1.03%
to –0.77%). Estimated mean treatment differences for
liraglutide vs sitagliptin were –0.34% for 1.2 mg (P<.0001)
and –0.60% for 1.8 mg (P<.0001). Nausea was more common with liraglutide (21% with 1.2 mg and 27% with 1.8
mg) than with sitagliptin (5%), and minor hypoglycemia
was observed in approximately 5% of patients in each treatment group.31 Both the DURATION-2 and the liraglutide vs
sitagliptin study demonstrate the superiority of GLP-1 receptor agonists favoring reductions in HbA1c, fasting glucose
levels, and weight over DPP-4 inhibitors in patients with
type 2 DM.
EFFECTS OF GLP-1 RECEPTOR AGONISTS ON
GLUCOSE CONTROL AND OTHER CV RISK FACTORS
Treatment with GLP-1 receptor agonists offers an effective alternative to other currently available hypoglycemic
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4. INCRETIN SYSTEM IN TREATMENT OF TYPE 2 DM
agents for patients with type 2 DM.32 In pivotal phase 3
studies, exenatide given for 30 weeks significantly reduced
HbA1c levels in patients with type 2 DM who were unable
to achieve adequate glycemic control with maximally effective doses of a sulfonylurea (exenatide, –0.86% vs
+0.12% with placebo; P≤.0001),33 metformin (exenatide,
–0.78% vs +0.08% with placebo; P<.002),34 or combined
metformin and sulfonylurea therapy (exenatide, –0.8% vs
+0.2% with placebo; P<.0001).35 Exenatide also resulted in
weight loss in each of the 3 studies in the range of –1.6 to
–2.8 kg, which was markedly better than weight loss seen
with placebo. The most common adverse events (AEs) reported were mild-to-moderate gastrointestinal disorders
and mild-to-moderate hypoglycemia.33-35
In an open-ended, open-label extension trial of the 3
placebo-controlled phase 3 trials noted in this article, 217
patients completed 3 or more years of exenatide therapy.36
Exenatide treatment was associated with sustained improvements in glycemic control and reductions in CV risk
factors. Reductions in HbA1c from baseline to week 12
(–1.1%) were maintained for 3 years (–1.0%; P<.0001).
Body weight decreased progressively from baseline such
that the mean reduction at 3 years was –5.3 kg (P<.0001),
with 84% of patients losing weight, and 50% of patients
losing 5% or more of their body weight. Total cholesterol
levels were significantly reduced (–5%; P=.0007), as were
triglyceride levels (–12%; P=.0003) and low-density lipoprotein cholesterol levels (–6%; P<.0001). High-density lipoprotein levels increased by 24% (P<.0001). Also, after 3
years, systolic and diastolic blood pressures were reduced
by –2% and –4%, respectively (P=.0063 and P<.0001,
respectively).36 Homeostasis model assessment of β-cell
function (HOMA-β) was also significantly improved from
baseline in 92 patients for whom data were available (baseline HOMA-β, 52.4% with an increase at 3 years to 70.1%;
P<.0001). Mild-to-moderate nausea was the most common
AE seen in 59% of patients and led to a 5% patient withdrawal rate. Hypoglycemia was the next most frequent AE
reported with 1 case of severe hypoglycemia occurring in a
patient who also received metformin and a sulfonylurea.36
Exenatide treatment for 52 weeks (n=36) significantly
improved β-cell function, as reflected by a 2.46-fold increase (95% CI, 2.09-2.90; P<.0001) in glucose- and arginine-stimulated C-peptide secretion compared with insulin
glargine in metformin-treated patients with type 2 DM.37
Both exenatide and insulin glargine reduced HbA1c levels
similarly (–0.8% and –0.7%, respectively). Body weight
was reduced significantly more with exenatide than with
insulin glargine (difference, –4.6 kg; P<.0001). Both agents
were generally well tolerated; mild-to-moderate nausea
was seen in 50% of exenatide-treated patients, whereas hypoglycemia was seen more frequently with insulin glargine
(24% vs 8%). The effects on β-cell function were not sustained after cessation of therapy, with a return to baseline
levels within 4 weeks.37
The beneficial effects of exenatide on HbA1c in patients
with type 2 DM are similar to those of insulin analogues.
However, exenatide has shown greater beneficial effects
on PPG excursions and lower risks of nocturnal and overall hypoglycemia. Barnett et al38 evaluated exenatide and
insulin glargine in 138 patients with type 2 DM not adequately controlled with metformin or a sulfonylurea. Although both agents reduced HbA1c levels by –1.36%, exenatide therapy resulted in weight loss, whereas patients
receiving insulin gained weight (between-group difference, –2.2 kg; P<.001). The PPG excursions (2-hour) were
significantly lower with exenatide (P≤.016) as were total
daily mean glucose excursions (P<.001).38 Exenatide was
compared with insulin glargine in 551 patients with DM
not adequately controlled with metformin and a sulfonylurea. Both drugs reduced HbA1c levels by –1.1%, but exenatide reduced PPG excursions more than did insulin.39
Finally, patients with type 2 DM who received metformin
and a sulfonylurea were randomized to receive exenatide
(n=253) or insulin aspart (n=248) for 52 weeks. There was
no difference between the 2 groups in HbA1c reduction (exenatide, –1.04% vs –0.89% for insulin). The PPG excursions were significantly lower for exenatide after morning
(P<.001), midday (P<.002), and evening meals (P<.001).40
Exenatide treatment provided an additional benefit of sustained weight loss, whereas insulin analogue therapy was
associated with weight gain.38-40
Exenatide once weekly (formulated with exenatide and
poly [d,l-lactic-co-glycolic acid] microspheres to extend
release; n=148) for 30 weeks provided significantly greater
improvements in glycemic control than exenatide twice daily
(n=147), with HbA1c reductions of –1.9% vs –1.5% (P=.0023).
Exenatide once weekly has yet to be FDA approved for clinical use. Both exenatide once weekly and twice daily resulted
in similar reductions in body weight (–3.7 vs –3.6 kg) without
increased risk of hypoglycemia (1 case among 186 patients
not receiving background sulfonylurea therapy and approximately 15% in each exenatide group receiving background
sulfonylurea therapy).41 The improvements in glycemic control, body weight, and cardiometabolic risk factors associated
with exenatide once weekly were sustained during 2 years of
treatment.42,43
Six large randomized, placebo- and/or active-controlled,
multicenter phase 3 trials of 26 or 52 weeks’ duration were
performed as part of the Liraglutide Effect and Action in
Diabetes (LEAD) program, which included both placebo
and active control groups.44-49 Most used double-blind,
double-dummy methods; however, LEAD-649 was open
label, as was one of the control arms (insulin glargine) in
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5. INCRETIN SYSTEM IN TREATMENT OF TYPE 2 DM
LEAD-5.46 In the LEAD program, liraglutide in therapeutic doses of 1.2 and 1.8 mg as monotherapy or combination
therapy reduced HbA1c levels from baseline by –0.8% to
–1.5%.
Improvements were also seen in blood pressure and
some CV risk factors.48 In LEAD-6, 464 patients were
randomized to receive liraglutide (n=233) or exenatide
(n=231) for 26 weeks, and their effects on glycemic control, body weight, and safety were evaluated. Liraglutide
was associated with better glycemic control (HbA1c reduction of –1.12% with liraglutide compared with –0.79% for
exenatide; P<.0001). Both drugs promoted similar weight
loss (–3.2 kg with liraglutide and –2.8 kg with exenatide).
Nausea was reported in 25.5% of patients receiving liraglutide and 28.0% of patients receiving exenatide. Although the incidence of nausea was similar initially, liraglutide-treated patients had less persistent nausea at week
26 compared with exenatide-treated patients (5 [3%] of 202
vs 16 [9%] of 186). Despite the lower overall reporting of
AEs in the liraglutide group compared with the exenatide
group (74.9% vs 78.9%), there were more serious (5.1%
vs 2.6%) and more severe (7.2% vs 4.7%) AEs in the liraglutide group.49
Interestingly, patients enrolled in the LEAD studies were
not permitted to down-titrate the dose of their study medications. If they developed nausea in association with their
drug they had to choose between withdrawing consent or
continuing with the study and living with their nausea. In
clinical practice, patients can be advised to reduce their dose
because fewer gastrointestinal adverse effects are associated with lower doses of GLP-1 receptor agonists.35,50 Some
investigators believe that nausea can be more prevalent in
patients using GLP-1 agonists who eat beyond their point of
satiety. Therefore, advising patients to stop eating if they feel
full might reduce the frequency of nausea.
Adding liraglutide once daily (1.2 or 1.8 mg) to a sulfonylurea for 26 weeks produced greater improvements
in glycemic control than rosiglitazone (–1.1% reduction
in HbA1c level for liraglutide vs –0.4% for rosiglitazone;
P<.0001) and greater weight loss (–0.2 kg with 1.8 mg of
liraglutide vs +2.1 kg for rosiglitazone; P<.0001) in patients with type 2 DM.44 In patients with type 2 DM receiving metformin, the addition of liraglutide, 1.2 or 1.8
mg, or glimepiride, 4 mg, once daily provided the same
improvements in glycemic control (–1.0% for all groups);
body weight decreased in both liraglutide groups in the
range of –1.8 to –2.8 kg compared with an increase of +1.0
kg with glimepiride (P<.0001), with a lower incidence of
minor hypoglycemia (3% with liraglutide vs 17% with
glimepiride; P<.001).45 Finally, liraglutide monotherapy in
a dose of 1.8 mg provided greater improvements in HbA1c
level (P<.05) and body weight (P<.05), with a lower inci-
dence of minor hypoglycemia (P<.05) than glimepiride, 8
mg once daily, monotherapy in patients with type 2 DM
treated for 52 weeks47 and 2 years.51
DPP-4 INHIBITORS
A number of clinical trials have evaluated the efficacy and
safety of the DPP-4 inhibitors in patients with type 2 DM.
Overall, such studies have shown that these compounds
have favorable effects on glycemic outcomes, have no consistent beneficial effects on lipid profiles, and are weight
neutral.26,32
Aschner et al52 studied 741 patients with type 2 DM
with a baseline HbA1c level of 8% who were randomized
to receive sitagliptin monotherapy (100 or 200 mg/d) or
placebo for 24 weeks. Sitagliptin produced significant
(P<.001) placebo-subtracted reductions in HbA1c (–0.79%
and –0.94% with the 100- and 200-mg doses, respectively) compared with placebo. Measures of β-cell function
(HOMA-β and proinsulin-insulin ratio) improved with
sitagliptin. No meaningful body weight changes were seen
in any of the groups. Sitagliptin was well tolerated after 24
weeks of treatment with no meaningful differences in AEs
between treatment groups.52
Nauck et al53 compared the efficacy and safety of sitagliptin with glipizide for 52 weeks in 588 patients with
type 2 DM not adequately controlled with metformin.
From a mean baseline HbA1c level of 7.5%, both agents
reduced HbA1c by –0.67%. Changes in fasting plasma glucose (FPG) from baseline were similar as well: –10 mg/dL
with sitagliptin and –7.5 mg/dL with glipizide. Sitagliptintreated patients lost an average of 1.5 kg of body weight
during the 52 weeks compared with a weight gain of 1.1
kg in glipizide-treated patients (significant between-group
difference, P<.001). More patients experienced hypoglycemic episodes with glipizide (32%) than with sitagliptin
(5%; P<.001). Seven patients receiving glipizide (1.2%)
and 1 patient receiving sitagliptin (0.2%) had hypoglycemic episodes that required medical assistance.53
When added to ongoing pioglitazone therapy in patients
with type 2 DM, sitagliptin significantly reduced the mean
change from baseline in between-group difference in HbA1c
(–0.7%; P<.001) and FPG (–17.7 mg/dL; P<.001) levels,
and more patients achieved a target HbA1c level of less than
7% with sitagliptin (45.4% vs 23.0%; P<.001) than with
placebo. Sitagliptin also reduced fasting proinsulin levels
(P=.009) and the proinsulin-insulin ratio (P<.001) compared with placebo. Treatment with sitagliptin was generally well tolerated. The incidence of drug-related clinical
AEs was similar between the 2 groups (9.1% vs 9.0%). The
number of patients discontinuing therapy because of drugrelated AEs was the same in both groups (0.6%).54
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6. INCRETIN SYSTEM IN TREATMENT OF TYPE 2 DM
Saxagliptin once daily or placebo was added to ongoing metformin therapy for 24 weeks in 743 patients
with type 2 DM inadequately controlled with metformin
alone.55 Saxagliptin, compared with placebo, resulted
in significant reductions in HbA1c levels (–0.6% for 10
mg/d vs +0.13% for placebo; P<.0001). Improvements
in β-cell function (as measured by HOMA-β) were also
noted. Finally, improvements in FPG, PPG, insulin, and
glucagon areas under the concentration time curve during
oral glucose tolerance testing (all P≤.001 vs placebo) were
observed with saxagliptin treatment. Monotherapy with
saxagliptin once daily produced improvements in HbA1c,
FPG, and PPG levels and was generally well tolerated in
treatment-naive patients with type 2 DM.56 The addition
of alogliptin (12.5 or 25 mg/d) or placebo was studied in
493 patients with type 2 DM not adequately controlled
with pioglitazone.57 Background therapy with metformin
or a sulfonylurea was continued. Alogliptin in either dose
significantly improved glycemic control after 26 weeks
(HbA1c reductions of –0.66% and –0.80% for alogliptin vs
–0.19% for placebo; P<.001) and was generally well tolerated. The AEs were similar across all treatment groups.
Cardiac events occurred more often in the group receiving alogliptin, 25 mg/d (6.5%), than in the group receiving
placebo (1.0%) or alogliptin, 12.5 mg/d (3.0%), although
these differences were not statistically significant. There
was no significant effect on body weight or the incidence
of hypoglycemia between the groups.57 When added to
ongoing metformin therapy, alogliptin once daily significantly decreased HbA1c (P<.001) and FPG levels (P<.001)
for 26 weeks with no increased risk of hypoglycemia or
weight gain.58
The effects of vildagliptin monotherapy on glycemic
control in patients with type 2 DM were similar to those
of acarbose monotherapy at 24 weeks, but vildagliptin had
better gastrointestinal tolerability.59 In treatment-naive patients with type 2 DM, vildagliptin monotherapy at dosages
of 50 mg once daily, 50 mg twice daily, and 100 mg once
daily produced significant decreases in HbA1c compared
with placebo (change from baseline, –0.8%, –0.8%, and
–0.9% vs –0.3% for placebo, respectively; P<.01 for all active groups vs placebo). Vildagliptin did not cause weight
gain and was associated with a low risk of hypoglycemia
at 24 weeks.60 The most common AEs with DPP-4 inhibitors were nasopharyngitis, headache, and increased risk of
urinary tract infection.32
The DPP-4 inhibitors appeared to improve short-term
surrogate measures of β-cell function (eg, HOMA-β and
proinsulin-insulin ratio) but did not seem to provide benefits over other agents with respect to β-cell function and
activity.61 However, long-term prevention of β-cell dysfunction with these agents needs to be studied.
CLINICAL PERSPECTIVES FOR PCPS WHEN
TREATING PATIENTS WITH INCRETIN THERAPY
The complexity of DM care coupled with the need to tailor
treatment recommendations to individual patients produces
wide variability in the provision of care.62 Balancing the
multiple goals of ideal DM care with the realities of patient
adherence, expectations, and circumstances is a major challenge for PCPs.
Understanding the basic principles of the pathophysiology of type 2 DM is important for rationale-based management of chronic hyperglycemia. In an online survey of 847
PCPs and specialized care physicians in the United States
and several European countries, the proportions of respondents familiar with key aspects of type 2 DM pathophysiologic features and newer treatment options were low.63 In
particular, overall familiarity was low for β-cell dysfunction (55%), glucagon (38%), and hepatic glucose output
(55%). Among specialized care physicians, 6% were not
familiar with the term β
. In the United
States, familiarity with the incretins and GLP-1 was higher
among specialized care physicians (69% and 74%, respectively) than among PCPs (5% and 6%, respectively). This
lack of understanding may influence physician prescribing
behavior and limit the application of pathophysiologybased therapy in individual patients with type 2 DM.63
Differences in the clinical effects of GLP-1 receptor
agonists and DPP-4 inhibitors on glycemic control, body
weight, and CV risk factors in patients with type 2 DM
may be partially related to differences in the degree of
GLP-1 receptor activation achieved with these compounds.
The pharmacological concentrations of GLP-1 receptor
agonists achieved with therapeutic administration may provide greater levels of GLP-1 receptor activation than the
physiologic levels achieved with DPP-4 inhibition.26,29 This
difference may explain the greater levels of PPG reduction,
stimulation of insulin secretion, and inhibition of glucagon
secretion observed with GLP-1 receptor agonists compared
with DPP-4 inhibitors, as well as the appetite suppression
and weight loss observed in patients treated with GLP-1
receptor agonists.26
SAFETY
GLP-1 RECEPTOR AGONISTS
The safety of GLP-1 receptor agonists has been examined
in clinical trials. Exenatide is associated with an increased
risk of hypoglycemia, primarily when used in combination with sulfonylureas. Compared with insulin or used in
combination with metformin, exenatide is not associated
with an increased risk of hypoglycemia.15,64,65 The most frequently reported AEs with exenatide are nausea and vomitS43
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7. INCRETIN SYSTEM IN TREATMENT OF TYPE 2 DM
ing; however, discontinuation rates of exenatide treatment
due to gastrointestinal AEs have been low and consistent
across studies.64 Similarly, the most common AEs reported
in the liraglutide registry clinical trials were gastrointestinal. Nausea, diarrhea, and vomiting were reported in 10%
to 30% of patients. One in 7 patients developed nausea,
which was transient and usually decreased to less than 10%
between weeks 6 and 12.48
In rats, once-daily subcutaneous administration of liraglutide has been found to induce thyroid C-cell hyperplasia, elevated calcitonin levels, and medullary thyroid
cancers after long-term administration of at least 8 times
the doses used in humans. In mice, only benign adenomas
were found under similar conditions. The findings raised
concern at the FDA, and a box warning has been included
in the liraglutide prescribing information that alerts physicians to the potential risk of liraglutide-induced thyroid Ccell tumors. However, to date there is no evidence linking
liraglutide to medullary thyroid cancers in humans. Investigators think that the differences in the C-cell stimulation
observed between nonhuman primates and humans may be
due to the absence or very low levels of GLP-1 receptor
agonist activity within human C cells.66
Structurally distinct GLP-1 receptor agonists, such
as liraglutide and exenatide, are associated with induction of antibodies. Nine percent of liraglutide-treated patients and 38% of twice-daily exenatide–treated patients
developed antibodies to the drugs.15,67 In a study of 295
patients with type 2 DM, exenatide once weekly resulted
in higher antibody titers than with exenatide twice daily.41
However, development of antibody titers did not interfere
with glycemic efficacy, and the antibody titers remained
constant for 6 to 14 weeks and then decreased during the
remaining 16 weeks of the study (all patients were followed up for 30 weeks).41 In the liraglutide clinical trials,
although the presence of antibodies does not seem to be
a major determinant of therapeutic effectiveness for most
patients, some individuals with very high antibody titers
may experience diminished therapeutic efficacy, angioedema, anaphylaxis, urticaria, or generalized pruritus. The
elevation in antibody titers does not appear to correlate
with a reduction in HbA1c levels over time. A total of 5%
of the patients enrolled in the LEAD registry trials developed cross-reacting antibodies to native GLP-1.67 From
a clinical standpoint, the true importance of antibody induction is unclear. Antibodies to therapeutic proteins can
compromise efficacy by neutralizing the medication and/
or triggering AEs, ranging from mild injection site reactions to life-threatening anaphylaxis. Therapeutic proteins
with a higher structural similarity to endogenous proteins
generally have a lower risk of both antibody formation and
higher antibody titer development. Liraglutide shares 97%
homology with human GLP-167 compared with exenatide,
which shares 53% homology.15
In the LEAD-6 open-label extension arm comparing the
safety and efficacy of liraglutide and exenatide, antibody
titers were obtained at weeks 0, 12, 26, 41, 78, and 79 before the daily dosage administration.68 After 78 weeks of
liraglutide therapy, 2.6% of patients had low-titer antibodies.69 Four patients who developed neutralizing antibodies
to liraglutide had HbA1c levels reduced by up to –1.9%
from baseline. However, after 26 weeks of exenatide use,
61% of patients developed antiexenatide antibodies. Those
who had high titers of neutralizing antibodies demonstrated
a minimal reduction in HbA1c (–0.1%) compared with individuals who had low titers of neutralizing antibodies, who
demonstrated a –1% HbA1c reduction. At the conclusion of
the study (week 78), only 3% of liraglutide-treated patients
had developed antibodies to the GLP-1 analogue. The HbA1c
level in this small subset of patients (n=4) decreased by an
additional –0.3% to –0.5%. In the LEAD-6 extension, 1%
of the liraglutide-treated patients had injection site reactions; 75% of these reactions occurred when the patients
were switched from exenatide to liraglutide and had positive exenatide antibody formation present. Only 2% of the
patients who switched from exenatide to liraglutide during
the extension phase developed mild site reactions. Therefore, the LEAD-6 trial demonstrates that the presence of
neutralizing antibodies may minimize the efficacy of medication. However, patients with high antibody titers who
were switched to liraglutide did not appear to experience
a compromise in their glycemic response. For liraglutidetreated patients, the presence of neutralizing antibodies appears to have minimal clinical importance.
Hypoglycemia is a primary factor that limits the success
of treatment with insulin and sulfonylureas in patients with
type 2 DM.70 Hypoglycemic events may lead to patient dissatisfaction with therapy, and medication adherence may
decrease. Patients who are older and those with impaired
hepatic or renal function with type 2 DM may be at an increased risk of treatment-related hypoglycemia. Therefore,
the use of therapies with a low likelihood of hypoglycemia
can be beneficial.
Patients with type 2 DM have a nearly 3-fold increased
risk of pancreatitis relative to patients without type 2 DM.
In younger patients with type 2 DM (age <45 years), the risk
of pancreatitis is increased more than 5-fold.71 According to
a health insurance claims–based drug safety system analysis, the use of exenatide in previously untreated patients
with type 2 DM is not associated with an increased risk
of pancreatitis compared with other antidiabetes drugs.72
During 1 year of follow-up, the risk of hospitalization for
a primary diagnosis of acute pancreatitis among patients
with type 2 DM was similar for initiators of treatment with
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8. INCRETIN SYSTEM IN TREATMENT OF TYPE 2 DM
exenatide (0.13%), sitagliptin (0.12%), and metformin and
glyburide (0.12%-0.13%).73
On the basis of postmarketing data, liraglutide has been
associated with pancreatitis, including fatal and nonfatal,
hemorrhagic, and necrotizing pancreatitis. A direct link
between GLP-1 agonists and pancreatitis has not been
established.73
On the basis of postmarketing data, exenatide has been
associated with pancreatitis, including fatal and nonfatal
hemorrhagic and necrotizing pancreatitis. After initiation
of an incretin mimetic agent and after dose increases, physicians are advised to observe patients carefully for signs
and symptoms of pancreatitis. Use of incretins should be
discontinued if pancreatitis is suspected, and appropriate management should be instituted. Exenatide therapy
should not be resumed if pancreatitis is confirmed.15
In phase 3A clinical trials of liraglutide, 8 cases of pancreatitis were reported, 7 of which were in patients treated
with liraglutide and 1 of which was in a patient treated
with a comparator. Five cases were diagnosed as acute, and
2 were chronic. Some patients had documented risk factors for pancreatitis, including obesity, alcohol use, high
triglyceride levels, use of concurrent medications (such as
angiotensin-converting enzyme inhibitors and thiazide diuretics), and the presence of cholelithiasis.73
Exenatide has not been shown to be nephrotoxic in preclinical or clinical studies; however, altered renal function
in patients taking exenatide has been noted in postmarketing reports. These include increased serum creatinine levels, renal impairment, worsened chronic renal failure, and
acute renal failure, sometimes requiring hemodialysis or
transplantation. Reversibility of renal dysfunction has been
observed in many cases with supportive treatment and discontinuation of use of the potentially causative agents, including exenatide. Exenatide should not be used in patients
with severe renal impairment (creatinine clearance <30
mL/min).15 Liraglutide is not metabolized by the kidney or
liver. The drug has not been studied specifically in patients
with hepatic or renal failure. However, no dose reductions
are recommended in these special patient populations.67
Patients with type 2 DM are at an increased risk of CV
disease. Consideration of the CV safety of antidiabetes
medications is an important aspect of disease management
in patients with type 2 DM. Compared with insulin therapy, treatment with exenatide was not associated with an
increased risk of CV disease and, in a recent meta-analysis,
was associated with a nonsignificant decreased risk of experiencing a CV event.74 The observation is consistent with
data from a long-term clinical trial extension demonstrating a beneficial effect of exenatide on CV risk factors.36
Whether the changes in CV risk factors seen with
GLP-1 agonists will have a substantial impact on future
CV outcomes is uncertain. Exenatide was the only incretin
agent used in the Action to Control Cardiovascular Risk
in Diabetes (ACCORD) study. An initial report of a 75%
reduction in mortality in exenatide-treated patients, adjusted for glycemia effect, is compelling because this was
the only antihyperglycemic agent that showed a significant
improvement in mortality among the various agents used in
ACCORD.75
DPP-4 INHIBITORS
The DPP-4 inhibitors are generally well tolerated, with low
rates of hypoglycemia and other AEs.32 The AEs associated
with DPP-4 inhibitors observed in clinical trials include
nasopharyngitis, headache, and increased risk of urinary
tract infection.32 The AEs reported with sitagliptin include
anaphylaxis, angioedema, and exfoliative skin conditions,
such as Stevens-Johnson syndrome.70 Dipeptidyl peptidase
4 cleaves multiple substrates in vivo, which may contribute
to the rare immunologic adverse effects of sitagliptin.70
From October 2006 through February 2009, 88 postmarketing cases of pancreatitis associated with sitagliptin have been reported through the FDA MedWatch program. As a result, the sponsor has revised the labeling for
sitagliptin.76
GUIDELINES, ALGORITHMS, AND
CLINICAL RECOMMENDATIONS
Expert consensus guidelines, such as those developed by
the American Diabetes Association/European Association
for the Study of Diabetes,5 the American Diabetes Association,77 and the American Association of Clinical Endocrinologists (AACE)/American College of Endocrinology
(ACE),78 provide valuable guidance for the management of
patients with type 2 DM. The AACE/ACE guidelines78 specifically address the following therapeutic principles: clinicians should minimize the risk and severity of hypoglycemia; GLP-1 receptor agonists are recognized as having a
greater effect on HbA1c and weight reduction than DPP-4
inhibitors; metformin is a cornerstone of therapy because
of its efficacy, safety, and cost and is usually the most appropriate choice for initial therapy unless a contraindication
(eg, renal failure) exists; sulfonylureas are considered lowpriority drugs because they tend to induce hypoglycemia,
favor weight gain, and have relatively short-term efficacy
(1-2 years); thiazolidinediones are well validated, effective,
and durable agents but have adverse effects that include
fluid retention, weight gain, congestive heart failure, and
bone fractures with long-term use; and α-glucosidase inhibitors, colesevelam, and glinides have utility in relatively
few, well-defined clinical situations based on their limited
efficacy and adverse effect profiles. Schwartz and Kohl79
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9. INCRETIN SYSTEM IN TREATMENT OF TYPE 2 DM
TABLE. Selection of Incretins Based on Actions and Patient Type
Action(s)
Patient type
GLP-1 receptor agonists
DPP-4 inhibitors
Fasting
hyperglycemia
↑Glucose-stimulated insulin secretion
↓Glucagon secretion
↑Glucose-stimulated insulin secretion
↓Glucagon secretion
Postprandial
hyperglycemia
↑Glucose-stimulated insulin secretion
↓Glucagon secretion
Restoration of biphasic response
Slow gastric emptying
↑Glucose-stimulated insulin secretion
↓Glucagon secretion
Restoration of biphasic response
Overweight
↓Body weight
Enhanced early satiety
Appetite suppression
Delayed satiety
Enhanced early satiety
Large appetite
Appetite suppression
Hypoglycemia
unawareness
Low incidence of hypoglycemia
Maintenance of hypoglycemia
counterregulation
Low incidence of hypoglycemia
Maintenance of hypoglycemia
counterregulation
Hyperlipidemia
↓Total cholesterol
↓Low-density lipoprotein cholesterol
↑High-density lipoprotein cholesterol
↓Triglycerides
↓Total cholesterol
↓Low-density lipoprotein cholesterol
↑High-density lipoprotein cholesterol
↓Triglycerides
DPP-4 = dipeptidyl peptidase 4; GLP-1 = glucagon-like peptide 1; ↑ = increased; ↓ = decreased.
From
,81 with permission from Quadrant HealthCom.
review the approach to the treatment of patients with type
2 DM based on the AACE/ACE algorithm in Figure 5 of
their article.
Management of patients with type 2 DM requires a
comprehensive assessment of lifestyle factors, including nutrition, weight loss goals, and exercise and activity
levels. Behavior modifications may be needed to improve
glycemic control and to reduce the long-term risk of complications. In addition to other important topics, patients
should be taught the importance of flexible meal planning
and the effects of caffeine, alcohol, and glycemic index on
blood glucose levels. Regular exercise should be encouraged for its beneficial effects on glycemic control, body
weight, and CV risk factors.77
Patients should understand the importance of medication
adherence, blood glucose monitoring, and other aspects of
DM management. Patients facing the prospects of long-term
medical treatment and lifestyle changes may benefit from
the establishment of highly specific behavior outcome goals
and short-term behavior targets.80 Adhering to DM treatment regimens may be enhanced with telephone calls and
reminder cards, minimization of delays during office visits,
and positive reinforcement from health care professionals.80
Incretin mimetics have been developed to address the
direct pathophysiologic defects observed in type 2 DM.
Because incretin mimetics work in a glucose-dependent
manner, they are likely to reduce hyperglycemia safely
without causing hypoglycemia. In the process of restoring
β-cell function, these agents can allow patients to achieve
an HbA1c level less than 7% (approximately 45%-50% of
patients receiving monotherapy and approximately 25%40% of patients receiving incretins in combination therapy
achieve an HbA1c level <7%) without experiencing weight
gain or hypoglycemia.
Implementation of incretin therapy in patients with type
2 DM requires careful consideration of numerous patient
factors. Loss of β-cell function is significant in patients
with prediabetes conditions and type 2 DM.16 Although the
possible long-term beneficial effects of incretins on β-cell
function remain uncertain, preservation of remaining β-cell
function is a reasonable therapeutic goal in patients at risk
of chronic hyperglycemia. Patients unaware of their hypoglycemia may also benefit from treatment with incretins
because these agents are associated with a low incidence
of hypoglycemia. The weight-reduction potential of GLP-1
receptor agonists and the weight-neutral effects of DPP-4
inhibitors may have important implications for certain patients with type 2 DM and may serve as motivating factors
to enhance treatment adherence.81 The AACE/ACE 2009
guidelines recommend that higher priority be given to the
use of GLP-1 receptor agonists and DPP-4 inhibitors because of their effectiveness and overall safety profiles.78
Recommendations for selecting incretins based on physiologic actions and patient type are given in the Table.81
CONCLUSION
Primary care physicians must be kept informed of evolving concepts in DM pathophysiology and newer therapies
for patients with type 2 DM. Understanding the clinical
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10. INCRETIN SYSTEM IN TREATMENT OF TYPE 2 DM
implications of the similarities and differences between
the GLP-1 receptor agonists and DPP-4 inhibitors is an
important aspect of therapeutic decision making and provides the best opportunity for successful individualization
of therapy in these patients. The GLP-1 receptor agonists
target the underlying metabolic defects of type 2 DM and
have provided clinical benefits beyond glucose control,
including improvements in body weight and CV risk factors and preservation of β-cell function in clinical trials.
The DPP-4 inhibitors also work to correct the underlying
incretin defect in patients with type 2 DM. The incretinbased therapies are an important addition to the antidiabetes treatment armamentarium for the management of type
2 DM.
CLINICAL PEARLS
HbA1c levels, effectively help patients reach their targeted
HbA1c level, lower FPG and PPG levels, improve β-cell
function, reduce weight, and improve markers for CV risk
in patients with type 2 DM.
most common adverse effect of GLP-1 receptor agonists is
mild, transient nausea; patients should also be monitored
for the development of pancreatitis. The DPP-4 inhibitors
can cause rashes, headaches, and upper respiratory tract infections. The long-term safety profile of these agents has
not yet been defined.
tions, GLP-1 receptor agonists have a more potent pharmacological effect on lowering HbA1c levels and effecting
weight loss than do the DPP-4 inhibitors.
abetes agents, such as GLP-1 receptor agonists and DPP-4
inhibitors, that target the pathophysiology of type 2 DM is
being investigated for its ability to slow disease progression and prevent long-term complications.
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